tbuckley/cabot-search huggingface dataset:
Reply to: Effect of prone positioning without mechanical ventilation in COVID-19 patients with acute respiratory failure
Authors: Orlando R. Pérez-Nieto, Eder I. Zamarron-Lopez, Josué L. Medina Estrada, Jesús Salvador Sánchez-Diaz, Manuel A. Guerrero-Gutiérrez, Diego Escarraman-Martinez, Raúl Soriano-Orozco
Journal: European Respiratory Journal (2022)

We have read the letter by Yanfei Shen and co-workers, and appreciate their interest in our study of awake prone positioning (APP) in non-intubated patients with acute hypoxaemic respiratory failure (AHRF) due to coronavirus disease 2019 (COVID-19). We would like to add a few comments to their purposeful remarks. Several questions on the efficacy of awake prone positioning for hypoxaemic respiratory failure remain unanswered. Research targeting those questions is needed. <https://bit.ly/3xmbNPP>
Changes in cardiopulmonary exercise capacity and limitations 3–12 months after COVID-19
Authors: Charlotte Björk Ingul, Anne Edvardsen, Turid Follestad, Divna Trebinjac, Odd Andre Wathne Ankerstjerne, Eivind Brønstad, Øystein Rasch-Halvorsen, Bernt Aarli, Håvard Dalen, Bjarne Martens Nes, Tøri Vigeland Lerum, Gunnar Einvik, Knut Stavem, Ingunn Skjørten
Journal: European Respiratory Journal (2022)

To describe cardiopulmonary function during exercise 12 months after hospital discharge for coronavirus disease 2019 (COVID-19), assess the change from 3 to 12 months, and compare the results with matched controls without COVID-19.In this prospective, longitudinal, multicentre cohort study, hospitalised COVID-19 patients were examined using a cardiopulmonary exercise test (CPET) 3 and 12 months after discharge. At 3 months, 180 performed a successful CPET, and 177 did so at 12 months (mean age 59.3 years, 85 females). The COVID-19 patients were compared with controls without COVID-19 matched for age, sex, body mass index and comorbidity. Main outcome was peak oxygen uptake (V'O2 peak).Exercise intolerance (V'O2 peak <80% predicted) was observed in 23% of patients at 12 months, related to circulatory (28%), ventilatory (17%) and other limitations including deconditioning and dysfunctional breathing (55%). Estimated mean difference between 3 and 12 months showed significant increases in V'O2 peak % pred (5.0 percentage points (pp), 95% CI 3.1-6.9 pp; p<0.001), V'O2 peak·kg-1 % pred (3.4 pp, 95% CI 1.6-5.1 pp; p<0.001) and oxygen pulse % pred (4.6 pp, 95% CI 2.5-6.8 pp; p<0.001). V'O2 peak was 2440 mL·min-1 in COVID-19 patients compared to 2972 mL·min-1 in matched controls.1 year after hospital discharge for COVID-19, the majority (77%), had normal exercise capacity. Only every fourth had exercise intolerance and in these circulatory limiting factors were more common than ventilator factors. Deconditioning was common. V'O2 peak and oxygen pulse improved significantly from 3 months.
Additional Benefits of Maintaining a Healthy Lifestyle After Quitting Smoking
Authors: Babalola Faseru, Pebbles Fagan, Kolawole S. Okuyemi
Journal: JAMA Network Open (2022)

Maki Inoue-Choi, PhD; Yesenia Ramirez, MPH; Ami Fukunaga, MPH; Charles E. Matthews, PhD; Neal D. Freedman, PhD
Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation
Authors: Anna S. Nam, Neville Dusaj, Franco Izzo, Rekha Murali, Robert M. Myers, Tarek H. Mouhieddine, Jesus Sotelo, Salima Benbarche, Michael Waarts, Federico Gaiti, Sabrin Tahri, Ross Levine, Omar Abdel-Wahab, Lucy A. Godley, Ronan Chaligne, Irene Ghobrial, Dan A. Landau
Journal: Nature Genetics (2022)
Analysis of Substance Use Disorder Treatment Admissions in the US by Sex and Race and Ethnicity Before and During the COVID-19 Pandemic
Authors: Jonathan H. Cantor, Christopher M. Whaley, Bradley D. Stein, David Powell
Journal: JAMA Network Open (2022)

This cross-sectional study examines the changes in treatment admissions for substance use disorder during the COVID-19 pandemic by sex and race and ethnicity.
Improved pea reference genome and pan-genome highlight genomic features and evolutionary characteristics
Authors: Tao Yang, Rong Liu, Yingfeng Luo, Songnian Hu, Dong Wang, Chenyu Wang, Manish K. Pandey, Song Ge, Quanle Xu, Nana Li, Guan Li, Yuning Huang, Rachit K. Saxena, Yishan Ji, Mengwei Li, Xin Yan, Yuhua He, Yujiao Liu, Xuejun Wang, Chao Xiang, Rajeev K. Varshney, Hanfeng Ding, Shenghan Gao, Xuxiao Zong
Journal: Nature Genetics (2022)

Abstract Complete and accurate reference genomes and annotations provide fundamental resources for functional genomics and crop breeding. Here we report a de novo assembly and annotation of a pea cultivar ZW6 with contig N50 of 8.98 Mb, which features a 243-fold increase in contig length and evident improvements in the continuity and quality of sequence in complex repeat regions compared with the existing one. Genome diversity of 118 cultivated and wild pea demonstrated that Pisum abyssinicum is a separate species different from P. fulvum and P. sativum within Pisum . Quantitative trait locus analyses uncovered two known Mendel’s genes related to stem length ( Le/le ) and seed shape ( R/r ) as well as some candidate genes for pod form studied by Mendel. A pan-genome of 116 pea accessions was constructed, and pan-genes preferred in P. abyssinicum and P. fulvum showed distinct functional enrichment, indicating the potential value of them as pea breeding resources in the future.
CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target
Authors: Quy Le, Brandon Hadland, Jenny L. Smith, Amanda Leonti, Benjamin J. Huang, Rhonda Ries, Tiffany A. Hylkema, Sommer Castro, Thao T. Tang, Cyd N. McKay, LaKeisha Perkins, Laura Pardo, Jay Sarthy, Amy K. Beckman, Robin Williams, Rhonda Idemmili, Scott Furlan, Takashi Ishida, Lindsey Call, Shivani Srivastava, Anisha M. Loeb, Filippo Milano, Suzan Imren, Shelli M. Morris, Fiona Pakiam, Jim M. Olson, Michael R. Loken, Lisa Brodersen, Stanley R. Riddell, Katherine Tarlock, Irwin D. Bernstein, Keith R. Loeb, Soheil Meshinchi
Journal: Journal of Clinical Investigation (2022)

The CBFA2T3-GLIS2 (C/G) fusion is a product of a cryptic translocation primarily seen in infants and early childhood and is associated with dismal outcome. Here, we demonstrate that the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML) and induces highly aggressive leukemia in xenograft models. Interrogating the transcriptome of C/G-CB cells and primary C/G AML identified a library of C/G-fusion-specific genes that are potential targets for therapy. We developed chimeric antigen receptor (CAR) T cells directed against one of the targets, folate receptor α (FOLR1), and demonstrated their preclinical efficacy against C/G AML using in vitro and xenograft models. FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns for toxicity that must be addressed for the clinical application of this therapy. Our findings underscore the role of the endothelial niche in promoting leukemic transformation of C/G-transduced CB HSPCs. Furthermore, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy.
Neonatal hyperoxia in mice triggers long-term cognitive deficits via impairments in cerebrovascular function and neurogenesis
Authors: Marissa A. Lithopoulos, Xavier Toussay, Shumei Zhong, Liqun Xu, Shamimunisa B. Mustafa, Julie Ouellette, Moises Freitas-Andrade, Cesar H. Comin, Hayam A. Bassam, Adam N. Baker, Yiren Sun, Michael Wakem, Alvaro G. Moreira, Cynthia L. Blanco, Arul Vadivel, Catherine Tsilfidis, Steven R. Seidner, Ruth S. Slack, Diane C. Lagace, Jing Wang, Baptiste Lacoste, Bernard Thébaud
Journal: Journal of Clinical Investigation (2022)

Preterm birth is the leading cause of death in children under 5 years of age. Premature infants who receive life-saving oxygen therapy often develop bronchopulmonary dysplasia (BPD), a chronic lung disease. Infants with BPD are at a high risk of abnormal neurodevelopment, including motor and cognitive difficulties. While neural progenitor cells (NPCs) are crucial for proper brain development, it is unclear whether they play a role in BPD-associated neurodevelopmental deficits. Here, we show that hyperoxia-induced experimental BPD in newborn mice led to lifelong impairments in cerebrovascular structure and function as well as impairments in NPC self-renewal and neurogenesis. A neurosphere assay utilizing nonhuman primate preterm baboon NPCs confirmed impairment in NPC function. Moreover, gene expression profiling revealed that genes involved in cell proliferation, angiogenesis, vascular autoregulation, neuronal formation, and neurotransmission were dysregulated following neonatal hyperoxia. These impairments were associated with motor and cognitive decline in aging hyperoxia-exposed mice, reminiscent of deficits observed in patients with BPD. Together, our findings establish a relationship between BPD and abnormal neurodevelopmental outcomes and identify molecular and cellular players of neonatal brain injury that persist throughout adulthood that may be targeted for early intervention to aid this vulnerable patient population.
A humanized minipig model for the toxicological testing of therapeutic recombinant antibodies
Authors: Tatiana Flisikowska, Jerome Egli, Krzysztof Flisikowski, Marlene Stumbaum, Erich Küng, Martin Ebeling, Roland Schmucki, Guy Georges, Thomas Singer, Mayuko Kurome, Barbara Kessler, Valeri Zakhartchenko, Eckhard Wolf, Felix Weber, Angelika Schnieke, Antonio Iglesias
Journal: Nature Biomedical Engineering (2022)

Abstract The safety of most human recombinant proteins can be evaluated in transgenic mice tolerant to specific human proteins. However, owing to insufficient genetic diversity and to fundamental differences in immune mechanisms, small-animal models of human diseases are often unsuitable for immunogenicity testing and for predicting adverse outcomes in human patients. Most human therapeutic antibodies trigger xenogeneic responses in wild-type animals and thus rapid clearance of the drugs, which makes in vivo toxicological testing of human antibodies challenging. Here we report the generation of Göttingen minipigs carrying a mini-repertoire of human genes for the immunoglobulin heavy chains γ1 and γ4 and the immunoglobulin light chain κ. In line with observations in human patients, the genetically modified minipigs tolerated the clinically non-immunogenic IgG1κ-isotype monoclonal antibodies daratumumab and bevacizumab, and elicited antibodies against the checkpoint inhibitor atezolizumab and the engineered interleukin cergutuzumab amunaleukin. The humanized minipigs can facilitate the safety and efficacy testing of therapeutic antibodies.
Cellular and transcriptional dynamics of human neutrophils at steady state and upon stress
Authors: Elisa Montaldo, Eleonora Lusito, Valentina Bianchessi, Nicoletta Caronni, Serena Scala, Luca Basso-Ricci, Carla Cantaffa, Alice Masserdotti, Mattia Barilaro, Simona Barresi, Marco Genua, Francesco Maria Vittoria, Giulia Barbiera, Dejan Lazarevic, Carlo Messina, Elisabetta Xue, Sarah Marktel, Cristina Tresoldi, Raffaella Milani, Paola Ronchi, Salvatore Gattillo, Luca Santoleri, Raffaella Di Micco, Andrea Ditadi, Giulio Belfiori, Francesca Aleotti, Matteo Maria Naldini, Bernhard Gentner, Elisa Gardiman, Nicola Tamassia, Marco Antonio Cassatella, Andrés Hidalgo, Immanuel Kwok, Lai Guan Ng, Stefano Crippa, Massimo Falconi, Francesca Pettinella, Patrizia Scapini, Luigi Naldini, Fabio Ciceri, Alessandro Aiuti, Renato Ostuni
Journal: Nature Immunology (2022)
A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma
Authors: Emmanuel Bachy, Steven Le Gouill, Roberta Di Blasi, Pierre Sesques, Guillaume Manson, Guillaume Cartron, David Beauvais, Louise Roulin, François Xavier Gros, Marie Thérèse Rubio, Pierre Bories, Jacques Olivier Bay, Cristina Castilla Llorente, Sylvain Choquet, René-Olivier Casasnovas, Mohamad Mohty, Stéphanie Guidez, Magalie Joris, Michaël Loschi, Sylvain Carras, Julie Abraham, Adrien Chauchet, Laurianne Drieu La Rochelle, Bénédicte Deau-Fischer, Olivier Hermine, Thomas Gastinne, Jean Jacques Tudesq, Elodie Gat, Florence Broussais, Catherine Thieblemont, Roch Houot, Franck Morschhauser
Journal: Nature Medicine (2022)

Abstract Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). In this study, we analyzed the outcome of 809 patients with R/R DLBCL after two or more previous lines of treatment who had a commercial chimeric antigen receptor (CAR) T cells order for axi-cel or tisa-cel and were registered in the retrospective French DESCAR-T registry study ( NCT04328298 ). After 1:1 propensity score matching ( n = 418), the best overall response rate/complete response rate (ORR/CRR) was 80%/60% versus 66%/42% for patients treated with axi-cel compared to tisa-cel, respectively ( P &lt; 0.001 for both ORR and CRR comparisons). After a median follow-up of 11.7 months, the 1-year progression-free survival was 46.6% for axi-cel and 33.2% for tisa-cel (hazard ratio (HR) = 0.61; 95% confidence interval (CI), 0.46–0.79; P = 0.0003). Overall survival (OS) was also significantly improved after axi-cel infusion compared to after tisa-cel infusion (1-year OS 63.5% versus 48.8%; HR = 0.63; 95% CI, 0.45–0.88; P = 0.0072). Similar findings were observed using the inverse probability of treatment weighting statistical approach. Grade 1–2 cytokine release syndrome was significantly more frequent with axi-cel than with tisa-cel, but no significant difference was observed for grade ≥3. Regarding immune effector cell-associated neurotoxicity syndrome (ICANS), both grade 1–2 and grade ≥3 ICANS were significantly more frequent with axi-cel than with tisa-cel. In conclusion, our matched comparison study supports a higher efficacy and also a higher toxicity of axi-cel compared to tisa-cel in the third or more treatment line for R/R DLBCL.
SIRT1 inactivation switches reactive astrocytes to an antiinflammatory phenotype in CNS autoimmunity
Authors: Weifeng Zhang, Dan Xiao, Xing Li, Yuan Zhang, Javad Rasouli, Giacomo Casella, Alexandra Boehm, Daniel Hwang, Larissa L.W. Ishikawa, Rodolfo Thome, Bogoljub Ciric, Mark T. Curtis, Abdolmohamad Rostami, Guang-Xian Zhang
Journal: Journal of Clinical Investigation (2022)

Astrocytes are highly heterogeneous in their phenotype and function, which contributes to CNS disease, repair, and aging; however, the molecular mechanism of their functional states remains largely unknown. Here, we show that activation of sirtuin 1 (SIRT1), a protein deacetylase, played an important role in the detrimental actions of reactive astrocytes, whereas its inactivation conferred these cells with antiinflammatory functions that inhibited the production of proinflammatory mediators by myeloid cells and microglia and promoted the differentiation of oligodendrocyte progenitor cells. Mice with astrocyte-specific Sirt1 knockout (Sirt1-/-) had suppressed progression of experimental autoimmune encephalomyelitis (EAE), an animal model of CNS inflammatory demyelinating disease. Ongoing EAE was also suppressed when Sirt1 expression in astrocytes was diminished by a CRISPR/Cas vector, resulting in reduced demyelination, decreased numbers of T cells, and an increased rate of IL-10-producing macrophages and microglia in the CNS, whereas the peripheral immune response remained unaffected. Mechanistically, Sirt1-/- astrocytes expressed a range of nuclear factor erythroid-derived 2-like 2 (Nfe2l2) target genes, and Nfe2l2 deficiency shifted the beneficial action of Sirt1-/- astrocytes to a detrimental one. These findings identify an approach for switching the functional state of reactive astrocytes that will facilitate the development of astrocyte-targeting therapies for inflammatory neurodegenerative diseases such as multiple sclerosis.
Differences in Cancer Phenotypes Among Frequent <i>CHEK2</i> Variants and Implications for Clinical Care—Checking <i>CHEK2</i>
Authors: Brittany L. Bychkovsky, Nihat B. Agaoglu, Carolyn Horton, Jing Zhou, Amal Yussuf, Parichehr Hemyari, Marcy E. Richardson, Colin Young, Holly LaDuca, Deborah L. McGuinness, Rochelle Scheib, Judy E. Garber, Huma Q. Rana
Journal: JAMA Oncology (2022)

Germline CHEK2 pathogenic variants (PVs) are frequently detected by multigene cancer panel testing (MGPT), but our understanding of PVs beyond c.1100del has been limited.To compare cancer phenotypes of frequent CHEK2 PVs individually and collectively by variant type.This retrospective cohort study was carried out in a single diagnostic testing laboratory from 2012 to 2019. Overall, 3783 participants with CHEK2 PVs identified via MGPT were included. Medical histories of cancer in participants with frequent PVs, negative MGPT (wild type), loss-of-function (LOF), and missense were compared.Participants were stratified by CHEK2 PV type. Descriptive statistics were summarized including median (IQR) for continuous variables and proportions for categorical characteristics. Differences in age and proportions were assessed with Wilcoxon rank sum and Fisher exact tests, respectively. Frequencies, odds ratios (ORs), 95% confidence intervals were calculated, and P values were corrected for multiple comparisons where appropriate.Of the 3783 participants with CHEK2 PVs, 3473 (92%) were female and most reported White race. Breast cancer was less frequent in participants with p.I157T (OR, 0.66; 95% CI, 0.56-0.78; P<.001), p.S428F (OR, 0.59; 95% CI. 0.46-0.76; P<.001), and p.T476M (OR, 0.74; 95% CI, 0.56-0.98; P = .04) PVs compared with other PVs and an association with nonbreast cancers was not found. Following the exclusion of p.I157T, p.S428F, and p.T476M, participants with monoallelic CHEK2 PV had a younger age at first cancer diagnosis (P < .001) and were more likely to have breast (OR, 1.83; 95% CI, 1.66-2.02; P < .001), thyroid (OR, 1.63; 95% CI, 1.26-2.08; P < .001), and kidney cancer (OR, 2.57; 95% CI, 1.75-3.68; P < .001) than the wild-type cohort. Participants with a CHEK2 PV were less likely to have a diagnosis of colorectal cancer (OR, 0.62; 95% CI, 0.51-0.76; P < .001) compared with those in the wild-type cohort. There were no significant differences between frequent CHEK2 PVs and c.1100del and no differences between CHEK2 missense and LOF PVs.CHEK2 PVs, with few exceptions (p.I157T, p.S428F, and p.T476M), were associated with similar cancer phenotypes irrespective of variant type. CHEK2 PVs were not associated with colorectal cancer, but were associated with breast, kidney, and thyroid cancers. Compared with other CHEK2 PVs, the frequent p.I157T, p.S428F, and p.T476M alleles have an attenuated association with breast cancer and were not associated with nonbreast cancers. These data may inform the genetic counseling and care of individuals with CHEK2 PVs.
Human immunodeficiency virus infection may be a contributing factor to monkeypox infection: Analysis of a 42-case series
Authors: Miguel Alpalhão, Diogo Sousa, Joana Vieitez Frade, João Patrocínio, Pedro Miguel Garrido, Catarina Correia, Cláudia Brazão, Dora Mancha, Maria Sofia Núncio, Isabel Lopes Carvalho, Ana Pelerito, Maria José Borrego, Paulo Filipe
Journal: Journal of the American Academy of Dermatology (2022)
Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy
Authors: Carsten Krieg, Lukas M Weber, Bruno Fosso, Marinella Marzano, Gary Hardiman, Monica M Olcina, Enric Domingo, Sahar El Aidy, Khalil Mallah, Mark D Robinson, Silvia Guglietta
Journal: Journal for ImmunoTherapy of Cancer (2022)

The role of inflammatory immune responses in colorectal cancer (CRC) development and response to therapy is a matter of intense debate. While inflammation is a known driver of CRC, inflammatory immune infiltrates are a positive prognostic factor in CRC and predispose to response to immune checkpoint blockade (ICB) therapy. Unfortunately, over 85% of CRC cases are primarily unresponsive to ICB due to the absence of an immune infiltrate, and even the cases that show an initial immune infiltration can become refractory to ICB. The identification of therapy supportive immune responses in the field has been partially hindered by the sparsity of suitable mouse models to recapitulate the human disease. In this study, we aimed to understand how the dysregulation of the complement anaphylatoxin C3a receptor (C3aR), observed in subsets of patients with CRC, affects the immune responses, the development of CRC, and response to ICB therapy. We use a comprehensive approach encompassing analysis of publicly available human CRC datasets, inflammation-driven and newly generated spontaneous mouse models of CRC, and multiplatform high-dimensional analysis of immune responses using microbiota sequencing, RNA sequencing, and mass cytometry. We found that patients' regulation of the complement C3aR is associated with epigenetic modifications. Specifically, downregulation of C3ar1 in human CRC promotes a tumor microenvironment characterized by the accumulation of innate and adaptive immune cells that support antitumor immunity. In addition, in vivo studies in our newly generated mouse model revealed that the lack of C3a in the colon activates a microbiota-mediated proinflammatory program which promotes the development of tumors with an immune signature that renders them responsive to the ICB therapy. Our findings reveal that C3aR may act as a previously unrecognized checkpoint to enhance antitumor immunity in CRC. C3aR can thus be exploited to overcome ICB resistance in a larger group of patients with CRC.